Novel 2{8 2-(1,3-diazacycloalk-2-enyl){9 benzophenone derivatives and novel 1,3-diazacycloalkenyl {8 2,1-a{9 {0 isoindole derivatives

ABSTRACT

Novel 2(2-(1,3-diazacycloalk-2-enyl))benzophenone compounds and novel 1,3-diazacycloalkenyl(2,1-a)isoindole compounds having useful analgesic and psychostimulant properties are prepared inter alia by condensation of o-benzoylbenzaldehydes with aliphatic diamines.

United States Patent [1 1 Metlesics et al.

1 1 NOVEL 2[2-(1,3-DIAZACYCLOALK-2- ENYL)]BENZOPIIENONE DERIVATIVES AND NOVEL 1,3-DIAZACYCLOALKENYL [2,l-A] ISOINDOLE DERIVATIVES [75] Inventors: Werner Metlesics, Clifton; Leo

Henryk Sternbach, Upper Montclair, both of NJ.

[73] Assignee: Hoffmann-La Roche Inc., Nutley,

[22] Filed: May 6, 1974 [21] Appl. No; 467,030

Related U.S. Application Data [60] Division of Ser. No. 639.315, May 18. 1967, abandoned, which is a continuation-in-part of Ser. No. 629,965, March 30. 1967. abandoned.

[52] U.S. Cl 260/309.6; 260/250 R; 260/251 R; 260/3261; 260/309.7; 260/591; 424/273 [51] Int. Cl C07d 49/34 1 Apr. 22, 1975 Primary E.\'aminerLewis Gotts Assistant E.\'aminer-Ethel G. Love Attorney, Agent, or FirmSamuel L. Welt; Bernard S.

Leon; William G. Isgro I 5 7 ABSTRACT Novel 2[2-( 1,3-diazacycloalk-2-eny1)]benzophenone compounds and novel 1,3-diazacyc1oalkenyll2,1- ajisoindole compounds having useful analgesic and psychostimulant properties are prepared inter alia by condensation of o-benzoylbenzaldehydes with aliphatic diamines.

3 Claims, No Drawings 1 2 wherein B represents an alkylene chain of 2 to 4 carbon NOVEL atoms in which one or more of the hydrogens can be K' replaced by lower alkyl; and R R R and R are each independently selected from the group consisting of by 5 drogen. halogen. lower alkyl, lower alkoxy, hydroxy i and triflu oromethyl and pharmaceutically acceptable NOVEL 1,3 DIAZACYCLOALKENYL [2 ,1-A] acid addition Salts thereof [SOINDOLE DERIVATIVES Compounds of formula I can undergo a prototropic shift to form compounds of the formula ENYLHBENZOPHENONE DERIVATIVES AND RELATED APPLICATIONS This is a division of application Ser. No. 639,315 filed May l8, i967, which in turn is a continuation-in-part- H ofU.S. Patent Application Ser. No. 626.965. filed Mar. 30, 1967, both now abandoned.

. I Ra BRlEF SUMMARY OF THE INVENTION r 4 This invention relates to a novel class of 2[2-( l ,3-diazacycl0alk-2-enyl)lbenzophenones and wherein R R R R and B each have the same meannovel l,3-diazacycloalkenyll2,l-a]isoindoles, novel ing as hereinabove.

processes and intermediates for the preparation of said The invention includes both tautomeric isomers as novel products and derivatives thereof and to the use 25 well as mixtures thereof. Tautomeric mixtures can be of said novel compounds as pharmaceuticals. More represented schematically as v as C RI. \NH R].v \N Ba a 0:0 v l I R2 R4 I I I 4 II particularly, the invention in its product aspect relates wherein R R R R and B each have the same meanto novel compounds of the formula a ing as hereinabove. I

45. DETAILED DESCRIPTION I l d a. h r R I B n one pro uct aspect this app lcation pertains to t e novel compounds of formulas l and II and derivatives thereof. Of particular interest are the compounds of I formulas l and II wherein B represents the group SS and R and R are each independently hydrogen'or lower alkyl. i.e. compounds of the formulas II-a wherein R,, R R and R each have the same meaning as hereinabove; and R and R are each independently hydrogen or lower alkyl and their phar'maceutically ac ceptable acid addition salts and tautomeric mixtures.

Compounds of formulas 1-0 and "-11 wherein R R R and R, are each hydrogen, i.e. compounds of the formulas wherein R and R each have the same meaning as hereinabove and their pharmaceutically acceptable acid addition salts and tautomeric mixtures constitute a preferred group.

In another product aspect this application pertains to the mixed ethers obtained from compounds of formula II and lower alkanols, i.e., compounds of the formula wherein R R R R and B each have the same meaning as hereinabove; and R is lower allgyl.

In .still another product aspect this application pertains to novel intermediates which will be more fully described with reference to the several processes for the preparation of compounds of formulasll and ll.

In one of its process aspects this application pertains to the preparation of compounds of'formulas I. ll and "-11 according to the following reaction sequence.

wherein R R R R R and B each have the same meaning as hereinabove.

The diol starting materials of formula V are known compounds or are readily obtainable in analogy to the preparation of the known compounds. The diol starting materials can be readily converted to the dicarbonyl intermediates of formula IV by oxidation techniques which are known per se such as, for example. using selenium dioxide and the like. as the oxidizing agent or by employing other oxidizing systems such as chromium trioxide in pyridine.

Treatment with an oxidizing agent can be conveniently carried out in an organic solvent such as, for example, dimethylformamide. dimethylsulfoxide; hydrocarbon solvents such as benzene, toluene; alkanols, eg. the lower alkanols, methanol, ethanol, etc.; acetic acid and the like. The oxidation reaction is preferably carried out at an elevated temperature suitably at a temperature between about room temperature and about 150C.

The intermediates of formula IV are themselves novel compounds and thus also constitute part of this invention. The intermediates of formula IV are readily condensed with diamines of the formula wherein B has the same meaning as hereinabove by mixing the components or by reacting them in the presence of an organic solvent such as benzene, toluene; alcohols such as lower alkanols and the like. The condensation is conveniently carried out at room temperature or above, preferably at a temperature between about C. and 150C. Alternatively, the diamine reactant of formula Xll can be employed as a salt thereof in which case the reaction is conducted by heating the mixture of reactants toa melt.

The reaction products. i.e., the compounds of formula III, can be readily oxidized, for example, by treatment with an oxidizing agent such as hydrogen peroxide or by exposure to gaseous oxygen at room temperature to give the peroxidesof formula Il-c which are readily reduced to the corresponding end products. The oxidation is conveniently carried out in an organic 4 LEI-r) I solvent such as alcohols, dimethylformamide, etc.. at room temperature. Higher or lower temperatures. e.g..

between about 20C. and C., can also be employed.

Since the peroxide intermediates readily undergo reduction, the reaction mixture obtained upon treatment of a compound of formula III with an oxidizing agent will ordinarily contain the end products along with the peroxide intermediate of formula "-0. Complete reduction of the peroxide can be accomplished without separating it from the reaction mixture and, in a preferred embodiment. the oxidation product is submitted directly to treatment with a reducing agent. If desired. however, the peroxide intermediate of formula "-0 can be separated from the reaction mixture obtained upon treatment of a compound of formula III with an oxidizing agent by any of the usual techniques, e.g., chromatographic separation, fractional crystallization, etc.

The reduction of the peroxide is conveniently carried out by employing any reducing agent conventionally used for the reduction of peroxides such as sodium sulfite. trialkylphosphite, etc. preferably in the presence of an organic solvent such asan alcohol, e.g., methanol, ethanol. etc.; dimethylformamide and the like, or when using a salt of the peroxide, the reduction can be carried out in an aqueous solvent, e.g., in an aqueous alcoholic solvent. The reduction is suitably carried out at room temperature or above, preferably at a temperature between about 20C. and 100C.

As noted above. the hydroxyl proton of a compound of formula ll can undergo a prototropic shift to form the corresponding isomeric end product of formula l. in solution the product obtained upon oxidation and reduction of an intermediate of formula III will ordinarily be a mixture of the tautomeric forms 1 and II. The relative amounts of the isomeric forms present is dependent upon such factors as the solvent system employed, the pH of the medium and the particular product1i.e., the meaning of B. R,, R R and R in formulas l and ll. For example, in a solution of chloroform the product obtained upon oxidation and reduction of 2,3- dihydro-S-phenyl-SH-imidazo[2,l-a]isoindole contains mixture of the isomers 2,3-dihydro-5-hydroxy-5- phenyl-5H-imidazol2,l-alisoindole and 2-(2-benzoylphenyl)-2-imidazoline in a ratio of about 1:1. The acid addition salts isolated in the ordinary manner from the reaction product of the oxidation and reduction of 2,3- dihydro-S-phenyI-SH-imidazol 2, l -a]isoindole are ordinarily obtained as structure I.

Compounds of formula ll-d are prepared from compounds of formula II by treating an acid addition salt, e.g.. the hydrochloride. hydrobromide or the like. of a formula ll compound with a lower alkanol preferably at an elevated temperature. The etherification can be suitably carried out using the lower alkanol as solvent or in the presence of an inert organic solvent such as ether and the like and preferably at a temperature between about room temperature and the reflux temperature of the reaction mixture, i.e., up to about 150C.

The novel compounds of formula lI-d as well as the Jed intermediates of formulas lI-c' and "I are obtained as racemates. It is intended to include in this invention all of the stereoisomeric forms whether they are obtained as racemic mixtures or as the separated optically active antipodes.

The intermediates of formulas Ill and II-c are also novel compounds which constitute part of this invention. Compounds of formula Ill are, in addition to being useful as intermediates in the preparation of compounds of formulas I and II, also useful as psychostimulant. anti-inflammatory and anti-pyretic agents.

Alternatively, the compounds of formulas III, II and I can be prepared according to the following reaction scheme:

R1 iHO R OOH VII VIII

II-c

R i oH I II wherein R R R R and B each have the same meaning as hereinabove.

According to one alternative synthesis outlined above the intermediates of formula III are prepared by cyclization of aphthalimidine of formula VlfThe cyclization of a phthalimidine of formula VI to form an intermediate of formula III is readily accomplished by treatment with a Lewis acid such as titanium chloride. boron trifluoride and'the like. The oxidation and reduction of the formula II intermediates to form the desired end products is accomplished by the procedures described above.

The reaction with Lewis acid is preferably carried out in the presence of an inert organic solvent, e.g., hydrocarbon solvents such as toluene. xylene and the like. and preferably at an elevated temperature suitably at the reflux temperature of the solvent employed. A preferred temperature range for the cyclization of the phthalimidines is a temperature between about 50C. to about 200C. The phthalimidine intermediates of formula VI are prepared by condensing a 3- phenylphthalidc of formula VII with a diamine of for mula XII. The S'phenyIphthaIides of formula VII and the diamines of formula X employed as starting materi-v als are known compounds or analogs of known compounds which are readily accessible in analogy to the known compounds.

The preparation of the formula VI intermediates is formula VIII are also novel compounds and thus constiacid, etc.,-or a Lewis acidsuch as zinc chloride, alumi num chloride. etc. Preferred catalysts for the reaction are the salts of ethylenediamin'e and pyridine suchas pyridinium hydrochloride and the like. It is preferred to carryout the reaction with an excess of the ethylenediamine reactant as solvent. However, inert organic soltemperatures between about 180C. and about 250C.

The preparation of the phthalimidines of formula VI does not itself constitute part of this invention and is given here-for the sake of completeness only.

Alternatively, the intermediates of formula III can be prepared from i the corresponding diazacycloalkenylisoindolones of formula VIII by reaction with an appropriate phenyl-organometallic derivative of the formula wherein R and R each have the same meaning as hereinabove; and 'Z is Li, MgBr, MgI, MgCl or the like.

The reaction with a phenyI-lithium derivative of formula XI can beconveniently carried out in the prestute a part of this invention. They are readily prepared by the condensation of a phthalaldehydic acid derivative of formula IX with an alkylene diamine of formula XII. The condensation reaction is conveniently carried out in the-presence of an inert organic solvent and preferably at an elevated temperature. Suitable temperatures for carrying out the condensation reaction are temperatures between about 20C. and about l00C. or the boiling point of the reaction mixture. As solvent for the condensation there can be suitably employed any of the usual organic solvents such as alcohols, hydrocarbons, ethers, etc.

The phthalaldehydic acid derivatives of formula IX are known starting materials or analogs of known compounds readily obtained by known processes.

In still another alternative process, the end products of formula I .can be obtained by oxidation of a lphenyI-2-aminoalkylisoindoline derivative as outlined below:

wherein B, R R R and R, are as defined hereinabove; and X is halogen, preferably chlorine, iodine or bromine or other similar leaving groups such as mesyloxy, tosyloxy and the like.

The oxidation is accomplished by treating with an oxidizing agent such as gaseous oxygen or chemical oxidants such as chromium trioxide in acetic acid and the like.

The reaction is preferably carried out in the presence of an organic solvent such as, for example,,hydrocarbon solvents, e.g., benzene, toluene or the like; alkanoic acids, e.g., acetic acid, propionic acid, etc.; ethers, alcohols and solvents such as dimethylformamide, etc. The reaction can be suitably accomplished at room temperature or at an elevated temperature, preferably at a temperature between about C. and 100C. The l-phenyI-2-aminoalkylisoindoline intermediates are prepared from the diols of formula V via a diester of formula V-a. The diesters ae obtained by the usual techniques for esterification, e.g., treating the diol with one of the ordinary esterifying agents such as a halo acid and halides such as phosphorous halide, thionyl halide. tosylhalide, etc. The diester of formula V-a is in turn converted to the l-phenyl-2- aminoalkylisoindoline intermediate of formula VI by condensing with a diamine of formula XII.

The reaction with diamine is conveniently carried out by adding the diester of formula V-a t0 the diamine at room temperature. Preferably, there is employed a large molar excess of diamine. The reaction can also be carried out at temperatures above or below room temperature, although for practical reasons it is preferred to operate at a temperature between about 0C. and 100C. The reaction is suitably carried out in the presence of an organic solvent such as, for example, benzene, methylene chloride, ether, tetrahydrofuran and the like; or, in the case where either or both of the reactants are liquid under the conditions employed in the reaction, the reaction is conveniently carried out in the absence of a solvent.

The preparation of the aminoalkylisoindolines of formula VI does not constitute part of this invention and is given here for the sake of completeness only.

As used throughout'this application the term lower alkyl" denotes straight and branched chain hydrocarbons containing 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, t.-butyl and the like. The term lo'wer alkoxy denotes lower alkylether groups wherein the alkyl group .is as defined above. The term halogen as. used herein includes all four halogens, i.e., chlorine, bromine, iodine and flourine.

Suitable salts of the compounds of formula I are prepared from nontoxic organic and inorganic acids. Suitable organic acids are, for example, maleic acid, fumaric acid, ascorbic acid, tartaric acid, salicylic acid, succinic acid, citric acid and the like. Suitable inorganic acids are, for example, the hydrohalic acids, e.g.,

l-phenyl-2- As has been indicated hereinabove the novel end products of this invention, i.e., the compounds of formula I and their pharmaceutically acceptable acid addition salts and the compounds of formula Il-d and their pharmaceutically acceptable acid addition salts, are useful as pyschostimulants. When administered, for example, orally, to animals such as mice they produce a direct-acting stimulant effect of long duration in sin.- gle doses in amounts ranging from 0.03 mg/kg to 50 mg/kg. By way of illustration the compound of Example l0, 2-(2-benzoylphenyl)-2-imidazoline, which has an LD in mice of 200 mg/kg p.o.; mg/kg s.c.; 77 mg/kg i.p.; and 37 mg/kg iv. (Prue. Soc. Exptl. Biol. Med., Vol. 57, pages 26]); reversed the hypothermia induced by reserpine in mice at a dose of 10 mg/kg s.c. (Med. Pharmacol. Exp., Vol] 12, pages 226-232, 1965); prevented the ptosis induced by tetrabenazene in mice at 0.06 mg/kg p.o. (Pletscher et al., Progress. Drug Research, Vol. II, page 417, I960); reversed the reserpine (I0 mg/kg s.c.) induced sedation in mice by increasing their locomotor activity at doses of 25-50 mg/kg p.o. (Med. Plzarmacol. E.rp., Vol. 12, pages 226-232, 1965); and potentiated the effects of fi-(3,4- dihydroxyphenyl)-a-alanine (DPOA) in mice at a dose of 6.25 mg/kg i.p. (Arc. Exp. Path. and Pharm., Vol. 140, page 237). The compounds of this invention have pyschostimulant effects qualitatively similar in many respects to those of imipramine and amphetamine which are well-known for their therapeutic uses and properties. Among other illustrative compounds of formulas I and ll-d which have been similarly tested and found to be qualitatively similar to 2-(2-benzoylphenyl)-2-imidazolir 1e, there can be named by way of exemplification the following:

5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5I-I- imidaz0[2,l-a]-isoindole;

2,3-dihydro-5-hydroxy-5-(4-methoxyphenyl)-5H- imidazo[2,l-a]-isoindole; and 2,3-dihydro-5-methoxy-5-phenyl-5 H-imidazo[2, l

a]is0indole. The activity of the claimed compounds of formulas l and II-d first demonstrated-by pharmacological evaluation in warm-blooded animals as indicated herein permits their use in therapy in the same general manner as imipramine or amphetamine, which latter compounds exhibit psychostimulant activity in the DOPA potentiation test at doses of 10 mg/kg i.p. and 1.0 mg/kg i.p. respectiv ely and in the ptosis'prevention test at doses of 60 mg/kg and 7.5 mg/kg respectively; Asa further illustration of the psychostimulant activity of the compounds of formulas I and lI-d, the compound of Example 21, 2,3,4,5-tetrahydro7-hydroxy-7-phenyl-7H- diazepino-[2,l-a]isoindole, which has an LD of 40 mg/kg i.v., prevented the ptosis induced by tetrabenazene at 0.4 mg/kg p.o.; reversed the hypothermia and hypometabolic effects induced by reserpine 10 mg/kg s.c.) in mice at 25 mg/kg p.o.; and potentiated the effects of DOPA in mice at a dose of 7.5 mg/kg i.p. The compounds of this invention thus demonstrate a pattern of activity associated with anti-depressants of known clinical efficacy and are similarly useful as psychostimulants in the treatment of depressed states, for example, in cases of simple depression or in cases of chronic nervous exhaustion.

In addition to their use as psychostimulants, the compounds of formulas l and ll-d are also useful as analgesic agents. By way of example, 2-(2-benzoylphenyl)-2- imidazoline, when submitted to standard pharmacological tests for analgesic properties, exhibited marked activity in the writhing test in mice at doses of 30.8 mg/kg p.o. and 5 mg/kg s.c. and anti-pyretic activity in rats at doses of 6.25 to 50 mg/kg p.o. The compound also showed potent anti-inflammatory activity in the inflamed rat foot test at 6.25 mg/kg p.o. and anti-edema activity in the Carrageenan anti-edema rat paw test at 6.25 mg/kg p.o. 1n the unanesthetized cat test for mus cle relaxants the compound was active at a dose of 2.5 mg/kg p.o. Based on the foregoing pharmacological tests in animals, the analgesic properties of the novel end products of this invention and particularly those of 2-(2-benzoylphenyl)-2-imidazoline can be likened to the analgesic properties of phenylbutazone which is well known for its therapeutic uses and properties. Compounds of formulas l and ll-a' are also useful as anorexigenic agents owing to their marked activity in the 4-hour anti-obesity test in rats wherein compounds of this class have demonstrated activity qualitatively similar to amphetamine. Compounds of this series have also demonstrated useful cardiovascular properties. For example, 2-(2-benzoylphenyl)-2-imidazoline in dogs at 4 mg/kg i.v. produced an increase in blood pressure of l mm. Hg after 2 minutes followed by gradual increase to 25 mm. Hg.

Compounds of formula I have also been found .to be active as anti-fungal agents. For example, they have been found to be active in vitro inCandida albic'ans, Microsporum auaouini and Triclwplzymn mentagrophyles. Accordingly, these compounds can be employed as anti-fungal agents in the treatment of pathogenic diseases caused by these organisms. They can, for example, be employed in the treatment of infectious fungal diseases such as moniliasis and dermatomycoses. For the treatment of fungal infections the compounds of formula l can be employed by applying a suitable composition containing about 0.1 mg. to about 5 g. of active material over the site of the infection. Suitable compositions are prepared by embodying a compound of formula I or a pharmaceutically acceptable salt thereof in a conventional carrier suitable for topical administration.

The novel end products of this invention, i.e., the compounds of formulas l and ll-d are mostly white crystalline odorless solids melting at temperatures in the order of 200C. They have basic properties and can be conveniently prepared in the form of their acid addition salts. Suitable salts are prepared as described hereinabove. The salts are characteristically white crystalline odorless solids soluble in water and have good stability underordinary conditions.

H The compounds of formulas l and lI-d, preferably in the form of their acid addition salts can be formulated into preparations suitable for administration by enteral or parenteral routes. They can be embodied in pharmaceutical unit dosage forms containing from about 0.5 mg. to about mg. of active material, i.e.. a compound of formulas I or ll-d or a salt thereof. Parenteral formulations will ordinarily contain less of the active substance than compositions intended for enteral, e.g., oral, administration. For oral administration the products of this invention can be prepared as tablets, capsules and the like containing about 10 to 50 mg. of active material. Formulations suitable for oral administration may be such as to provide either immediate, or in the alternative, sustained release of the active drug. In general, the formulations will be prepared with pharmaceutically acceptable adjuvant materials comprising from about 60 to about 98 per cent of the weight of the compositions in oral dosage form.

For parenteral administration the compounds can be formulated with a liquid diluent, for example, distilled water, in the preparation of a suitable parenteral dosage form. The preferred parenteral dosage form will contain from about 0.5 mg. to about 15 mg. of the active drug. In general, the compounds of this invention are formulatedwith conventional inert adjuvants into dosage forms suitable for enteral or parenteral administration following the conventional techniques and procedures of the prior art. Suitable dosage forms include tablets and capsules as well as solutions, emulsions and suspensions. The inert adjuvants which are suitable for use in preparing the various dosage forms include liquids and solids inorganic or organic in nature such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, Vaseline, etc. Additionally, the compounds can be used in combination with preservatives, stabilizers, wetting or emulsifying agents, salts for altering the osmotic pressure, buffers, etc. If desired, the compounds can be used also in admixture with other therapeutically valuable substances. Specific embodiments showing illustrative formulations 0f an exemplary compound of formula I follow.

Tablet Formulation Per Tablet Z-(Z-benzoylphenyl)-2-imidazoline 10.0 mg. Lactose 1 13.5 mg. Corn Starch 70.5 mg. Pregelatinized Com Stare 8.0 mg. Calcium Stearate 3.0 mg. Total Weight 205.0 mg.

Procedure 1. 2-(2-Benzoylphenyl)-2-imidazoline was mixed with the lactose, corn starch, and pregelatinized corn starch in a suitable size mixer.

2. The mix was passed through a Fitzpatrick Comminuting Machine fitted with a No. 1A screen and with knives forward.

3. The mix was returned to the mixer and moistened with water to a thick paste. The moist mass was passed through a- No. 12 screen and the moist granules were dried on paper-lined trays at 100F.

4. The dried granules were returned to the mixer, the calcium stearate was added and mixed well.

5. The granules were compressed at a tablet weight of 200 mg., usingstandard concave punches having a diameter of five-sixteenths inch.

Suppository Formulation Per 1.3 Gram 4 Suppository 2-( Z-henzoylphenyl)-2-imidazoline 0.025 gram Wecobee (E. F. Drew Company 1.230 gram M 522 Fifth Avenue New York. New York) Carnauba Wax 0.045 gram Capsule Formulation Per Capsule 2-( Z-henzoylphenyll-Z-imidazoline mg. Lactose 158 mg. (orn Starch 37 mg. Tale 5 m Total Weight 255 mg.

Procedure 1. 2-(2-Benzoylphenyl)-2-imidazoline was mixed with the lactose and corn starch in a suitable mixer.

2. The mixture was further blended by passing through a Fitzpatrick Comminuting Machine with a No. [A screen with knives forward.

3. The blended powder was returned to the mixer. the tale added and blended thoroughly. The mixture was then filled into No. 4 hard shell gelatin capsules on a Parke Davis capsulating machine (any similar type machine may be used).

Parenteral Formulation Per cc.

2-( 2-benzoylphenyl )-2-imidazoline 2.5 mg. Tartaric Acid q.s. ad pH 3.0

Phenol Anhydrous 4.5 mg.

Water for Injection. U.S.P. q.s. ad

Procedure 1. 2-(Z-Benzoylphenyl)-2-imidazoline was slurried in part of the water for injection.

2. 2-(2-Benzoylphenyl)Q-imidazoline was solubilized by slowly adding the tartaric acid to a pH of approximately 3.0.

3. The phenol anhydrous was then added.

4. The solution was filtered and allowed to stand for 24 hours. It was then filtered through an 02 Selas candle.

5. The solution was filled into desired size ampuls and sealed under an atmosphere of nitrogen.

6. All ampuls were inspected; those containing excessive amounts of fibers were rejected.

16 The drug was prepared in duplex ampuls. one containing the dry drug and the other containing the special diluent.

Dry Fill Ampul 5 cc.

Z-t Z-benzoylphenyl )-2-imida7.oline 25 mg.

Special Diluent 2 cc.

per ml. Tartaric acid 16 mg. Water for injection q.s. to 1.0 ml.

in a suitable container under an atmosphere of nitrogen the tartaric acid was dissolved in part of the water for injection. The solution was made to volume. filtered through an 02 Selas candle filter and filled into 2 cc. flint ampuls. The filling should be done under an atmosphere of nitrogen. The ampuls were sealed and sterilized at 2l2F. for 30 minutes. The ampuls were then inspected and those that leaked or contained fibers were discarded.

The drug in the preferred oral dosage form, i.e.. tablets or capsules containing 10 to 25 mg. of active material, will be administered under ordinary circumstances three or four times daily. The parenteral composition will be administered ordinarily one or two times daily. Effective dosages for the administration of compounds of this invention, i.e.. the compounds of formulas land ll-d, will. of course, depend in all instances upon the severity and individual characteristics of each case as determined by the prescribing practitioner. It will be understood that dosage forms containing larger and smaller quantities of the active drug ingredient are encompassed by the scope of this invention and that such dosage forms can be administered more or less frequently than indicated heretofore. It will be understood that dosage forms containing inert adjuvants in quantities which are greater or less than those indicated heretofore are also encompassed by this invention.

The invention will be more fully understood from the examples which follow. These examples are illustrative of the invention and are not to be construed as limitative thereof. All melting points are in degrees centigrade. Decomposition melting points were taken in a Thomas Hoover apparatus in open capillaries. They may vary il0 depending on the rate of heating.

EXAMPLE 1 Preparation of 2-benzoylbenzaldehyde A mixture of l g. of selenium dioxide-and l g. of Z-hydroxymethylbenzhydrol in 5 ml. of acetic acid was refluxed for 4% hours. The solution was cooled. filtered from selenium and the filtrate was poured into ice water and made alkaline with sodium hydroxide. Extraction with ether gave a yellow oil to which petroleum ether was added. White prisms were obtained which melted at 64-67. Ultraviolet maximum (2- propanol) at 226/7 mu (e 15.750) and 251/2 mu (e 18,500), inflexion at 294 mp.(e= 2.600); infrared absorption (CHCl at 1,665 cm and 1,705 cm.

Anal. Calcd. for C H O C. 79.98: H. 4.79 Found: C. 80.00; H. 4.68

EXAMPLE -2 Preparation of 2-(p-chlorobenzoyl)-benzaldehyde A solution of 18.6 g. of 4'-chloro-Zhydroxymethylbenzhydrol in 100 ml. of acetic acid and 10.4 g. selenium dioxide was refluxed for 2 hours. The mixture was poured on ice and made alkaline and extracted with ether. Concentration of the ether solution and addition of petroleum ether gave pale yellow prisms which after recrystallization from a mixture of ether and petroleum ether gave 2-(p-chlorobenzoyl)-benzaldehyde melting at l l2-l 13. Ultraviolet inflexion (2-propanol) at 225 my. (2 17.500) and maximum at 259 mu (6 22.500), infrared'absorption (CHCL at 1,670 cm and 1.705 cm".

Anal. Calcd. for C H CIO C; 68.72: H. .71

Found: C. 69.12. H. 1.50

EXAMPLE 3 Preparation of 2-(pTanisOyU-benzaldehyde A solution of 26 g. of 4' methoXy-Z-hydroxymethylbenzhydrol in 140 ml. of acetic acid and 1 4.5 g. sele' nium dioxide was refluxed for 2' hours. The mixture was filtered and the filtrate was made basic. An oil sepa-.,

rated which crystallized on standing and was collected.

Anal. Calcd. for C H CIO C. 68.72; H. 3.71 Found: C. 69.05: H. 3.87

EXAMPLE Preparation of 2-(4-bromobenzoyl)-benzaldehyde To a stirred solution of 8.2 g. of lithium aluminum hydride in 180ml. of tetrahydrofuran was added 40 g. of 2-(4-bromobenzoyl)-benzoic acid in the course of minutes. The mixture, afterbeing kept at- 25 for 2 hours, was cooled and ml. of a saturated sodium sulfate solution was added slowly. The mixture was filtered and the filtrate concentrated. The resulting oily residuewas dissolved in 32 ml. of acetic acid and 96 ml.

Recrystallization from a mixture of methylene chloride and petroleum ether gave off-white platelets melting at 90-9 1. Ultraviolet maxima (2-pr'opanol) at 221 my. (6

= 21,600), 258 mu (5 12.400) and 292 my. (5 17,00); infrared absorption (CHCl at 1.660cm and at 1.700 cm".

Anal. Calcd. for c.,-,H..0..1.-c. 74.99; H, 5.03 Found: c. 75.27; H; 5.26

EXAMPLE 4 Preparation of 2-benzoyl-4-chlorobenzaldehyde of xylene. This solution was added to a mixture of 17.1 g. of selenium dioxide in 60 ml. of acetic acid and 120 ml. of xylene and refluxed for 17 hours. During this time about 22 m1. of an aqueous phase had collected in a Dean Stark receiver. The solution was filtered, washed with sodium hydroxide and concentrated. Addition of petroleum ether gave white prisms melting at 1039-109". Recrystallization from a mixture of ether and petroleum ether raised the melting point to 1 10 -1l3. Ultraviolet inflexion (Z-propanol) at 225 mp. (e

= 17,500) and maximum at 261 mp. (e 22.200); infrared absorption (Cl-1C1 at 1,675 cm and 1.705 cm".

Anal. Calcd. for C H BrO C. 58.16; H. 3.14 1 Found: G. 57.86; H. 3.41

EXAMPLE 6 I 1 Preparation of 2,3-dihydro-5-phenyl-5H-imidazol2,l-a]isoind0le sulfate from 2'benzoylbenzaldehyde A solution of 21 g. of o-benzoylbenzaldehyde in 250 ml. of-toluene and 34 ml. of ethylenediamine was re fluxed for 24 hours; During this time 11.5 ml. of an 5 aqueous phase was separated in a Dean Stark receiver.

The reaction mixture was concentrated in vacuo to an orange oil which was dissolved in ethyl acetate and washed twice with water. The solution was dried and a solution of 5.3 ml. of concentrated sulfuric acid in A solution of 9.3 g. of 5-chloro-2 hydroxyrnethylconcentrated,,dissolved in 200 ml. of ethyl acetate and rnl. of ethanol was added. Acrystalline precipitate was collected which after recrystallization from a mixture-of methanol and ethyl acetate gave white prisms melting at 226-229 ,dec. Ultraviolet maxima (2- propanol) at 240 my. (6 15,000) and 276 mp. (e 5.400);'infrared absorption (KBr) 1.660 cm.

Anal. Calcd. for c,.H,.r' i'l ..H.so.: c. 57.82; H. 4.

= Found: C. 57.61: H 4

The hydrochloride of 2,3-dihydro-5-phenyl-5l-limidazo[ 2.1-a]-isoindole.was prepared from the corresponding base with aqueous 1 N hydrochloric acid. On recrystallization from a mixture of methanol and toluene,.white prisms melting at 226-228 dec. were ob- 19 tained. Nmr peaks (DMSO) at 8 3.6-4.6 (4H, multiplet), at 8 6.13 (1H. singlet), at 8 7.3-7.9 (9H. multiplet).

EXAMPLE 7 Preparation of 2,3-dihydro--phenyl-5H-imidazo[2. l -a lisoindole sulfate from 2-(2-aminoethyl)-3-phenylphthalimidine A solution of L2 ml. of titanium tetrachloride in 30 ml. of xylene was added at to a stirred solution of 2.5 g. of 2-(2-aminoethyl)-3-phenylphthalimidine in 150 ml. of xylene. The mixture was refluxed for 18 hours. cooled and washed with an aqueous solution of sodium carbonate. The xylene solution was extracted with 2N hydrochloric acid. The acidic extract was poured on ice and made alkaline with sodium hydroxide. The solutionwas extracted with ethyl acetate and the extract was concentrated. Addition of asolution of sulfuric acid in a mixture of ethanol and tetrahydrofuranand further dilution with ethyl acetate gave a crystalline precipitate. Recrystallization from a mixture of methanol and ethyl acetate gave the .product as white prisms melting at 225228 dec.

EXAMPLE 8 Preparation of 2.3-dihydro-S-hydroperoxy-S-phenyl-SH-imidazo-( 2, l

' a]isoindole The base liberated from 16.6 g. of 2.3-dihydro-5- phenyl-5H-imidazo[2.l-a ]isoindole sulfate was dissolved in 50 ml. of ethanol and ll ml. of a per cent by weight aqueous solution of hydrogen peroxide was added. The mixture was, stirred at 25 for hours. A crystalline crop was collected and placed on a column containing 250 g. of silica gel. Elution with a mixture of 1 part of methanol (volume) and 1 part of chloroform (volume) gave fractions from which on concentration a crystalline residue was obtained. Recrystallization from a mixture of methanol'and chloroform gave the product as white prisms melting at l67l68 dec. ultraviolet inflexions (Z-propanol) at 232 mp. (6' 14.000) and 290 my. (e= 2600). maxima at 269 mu (5 4000) and 275 mp. (e 4400 infrared absorption (KBr) at 1.665 cm".

EXAMPLE 9 Preparation of 5-(p-chlorophenyl)-2,3-dihydro-5-hydroperoxy-5H- imidazo[2,l-a]isoindole hydrochloride 1 Gram of 2-(p-chlorobenzoyl)-benzaldehyde was thoroughly mixed with 0.9 g. ofethylenediamine toluene sulfonate and heated in a metal bath (bath temperature. l20l25) for 1 minute. On cooling a deep yellow glassy material was obtained which on addition of methylene chloride, ethyl acetate and petroleum ether gave a crystalline precipitate which was treated with ice cold aqueous sodium hydroxide. The mixture was extracted with ether and the extract was exposed to air at 25 for 18 hours'fA crystalline crop was collected and suspended in methylene chloride. Addition of ethereal hydrogen chloride gave a crystalline material which Anal. Calcd. for c,..H..N. .o.; c. 72.16; H. 5.30. N. 10.52

Found: C. 72.09; H. 5.39: N. 10.22

Anal. Calcd. for c, ,-H,..N o. ..HC1; C. 63.47; H. 4.99: Cl. ll .7l

Found: C. 63.63; H. 4.832-Cl. ll.7

after recrystallization from a mixture of methanol and ether gve white prisms melting at ll77 dec. Ultraviolet inflexion (2-propanol) at 223 mu (6 21.800) and 279 my. (6 =5600). maximum at 243 mp. (e 15.500); infrared absorption (KBr) at 1670 cm.

C. 56.99; H. 418. CI, 2l.03; N. 8.3l Found: C. 57.l4; H. 4.15;

CI. 2l.()2; N. 8.30

Anal. Calcd. for C H ClN o HCl:

EXAMPLE 10 Preparation of 2-(2-benzoylphenyl)-2-imidazoline from 2,3-dihydro-5-phenyl-5H-imidazo[2,l-a]isoindole To a suspension of 8.5 g. of 2.3-dihydro-5-phenyl- 5H-imidazo-[2,l-alisoindole sulfate in water was added 50 ml. of 1N aqueous sodium hydroxide. Extraction with methylene chloride and concentration gave Anal. Calcd. for C H N O: C. 76.7 Found: C. 76.4

The 2 -(2-benzoylphenyl)-2-imidazoline prepared in this manner can form the isomeric 2,3-dihydro-5- hydroxy-5 phenyl-5H imidazo-[2,l-a]isoindole.

The hydrochloride was prepared by adding a solution of hydrogen chloride in methanol to a suspension of 2- '(2-benzoylphenyl).-2-imidazoline in methanol. Ether was added and the crystalline precipitate was collected.

Recrystallization from a-mixture of methanol and ether gave white'prisms melting at l 73l 76 dec. Ultraviolet maximum (Z-propanol) at 252 my. (6 13.600); infrared absorption (KBr) at 1,665 cm.

Anal. Calcd. for C H N- QHCI: Cl. 12.36 Found: Cl. 12.22

The hydrobromide was prepared by adding an aqueous solution of hydrobromic acid to a suspension of 2- (2-benzoylphenyl)-2-imidazoline in ethanol. Addition of ether gave a precipitate which after recrystallization from a mixture of ethanol and ether gave white platelets melting at 193-194 dec.

Anal. Calcd. for C,,;H N O.HBr: Br. Found: Br.

EXAMPLE 11 EXAMPLE 12 Preparation of 2-(2-benzoylphenyl)-2-imidazoline from 2.3-dihydro--hydroperoxy-5-phenyl-5H-imidazo[2.1- a]isoindole A solution of 0.1 g. of 2,3-dihydro-5-hydroperoxy-5- phenyl-SH-imidazo[2,l-a]isoindole and 0.33 g. of triethylphosphite in 20 ml. of ethanol was kept on a steam bath for 5 minutes, then 18 hours at 25. The solution was concentrated in vacuo and on addition of water 2- (Z-benzoylphenyl)-2-imidazoline was obtained.

EXAMPLE 13 Preparation of 2(2-benzoylphenyl)-2-imidazoline from 2-(2-aminoethyl)-l-phenylisoindoline A solution of 3.3 g. of chromium trioxide and 5.9 g. of 2-(2-aminoethyl)-l-phenylisoindoline in 250 ml. of acetic acid was stirred at 55-60 for 18 hours. The solution was cooled. poured on ice and made alkaline. Extraction with methylene chloride and removal of the solvent gave a brown oil which partly crystallized. Recrystallization from a mixture of chloroform and ethyl acetate gave the product as white prisms melting at 194l96 dec.

EXAMPLE 14 Preparation of 2-(2-aminoethyl)-l-phenylisoindoline A solution of 127 g. (0.59 mole) of 2-hydroxymethylbenzhydrol was dissolved in 900 ml. of benzene, 80 g. of anhydrous magnesium sulfate was added and the mixture was cooled in an ice bath. Hydrogen bromide was bubbled into the stirred solution until saturation which took about minutes. During this time the temperature of the solution was kept at l5l8. The ice bath was removed and the temperature was allowed to rise to 35 in the course of 1 hour. The mixture was heated for another hour at 4045 on a steam bath. During the whole time hydrogen bromide was passed into the solution to keep it saturated. The mixture was filtered and the solution was concentrated in vacuo to give a red oil which was dissolved in 200 ml. of benzene and added to 342 g. (5.7 moles) of ethylenediamine in the course of 15 minutes. During the addition the mixture was stirred and cooled to maintain a temperature of ca. 40. The mixture was stirred at 25 for minutes. Two layers were obtained and separated. The benzene layer was washed with water and concentrated in vacuo. The residual oil was dissolved in 250 ml. of ether. This solution was extracted twice with 300 ml. of cold 1N hydrochloric acid. The acidic aqueous phase was made alkaline with aqueous sodium hydroxide and extracted with 350 ml. of ether. The ethereal solution was washed with 250 ml. of water, dried and concentrated. The residue was an amber oil which crystallized on scratching. This material melted up to ca. 45.

By analogy there were also prepared the following:

2-(3-aminopropyl)-1-phenylisoindoline 2 (2-aminoethyl)-6-chloro-1-phenylisoindoline 2-(2-aminoethyl)-1-(p-methoxyphenyl)isoindoline 2-(4-aminobutyl)-l-phenylisoindoline 2-(2-amino-2-methylpropyl)-1-phenylisoindoline 2-( Z-aminopropyl 1 -phenylisoindoline 2-(2-aminoethyl)-1-(p-hydroxyphenyl)isoindoline.

EXAMPLE 15 Preparation of 2-[2-(4-chlorobenzoy1)phenyl]-2-imidazoline To 1 ml. of ethylenediamine was added 1 g. of 2-(pchlorobenzoyl)-benzaldehyde in small portions. An exothermic reaction took place and after 5 minutes the reaction mixture was poured into ice water. A yellow solid precipitate was collected and dissolved in methylene chloride. Ether and petroleum ether were added and the solution was shaken in air at 25. A crystalline precipitate was obtained which after recrystallization from a mixture of methylene chloride and methanol gave white needles melting at 178180 dec. Ultraviolet maxima (Z-propanol) at 223 mu (6 21,250), 268 ma (6 4300), 275 mp. (a 4320), inflexion at 290 ma (6 2200); infrared absorption (KBr) at 1660 cm.

Anal. Calcd. for C H ClN O: C. 67.49; H, 4.60

Found: C. 67.38; H, 4.56

The 2-[2-(4-chlorobenzoyl)phenyl]-2-imidazoline EXAMPLE 16 Preparation of 2-[2'-(4-anisoyl)phenyl]-2-imidazoline To 4 ml. of ethylenediamine was added 2 g. of 2-(panisoyl)-benzaldehyde in small portions. The solution was stirred for 10 minutes, poured into ice water and extracted with methylene chloride. The methylene chloride solution was concentrated, the residue was dissolved in ethanol and a stream of air was passed through the solution for 18 hours. A crystalline precipitate was collected and after recrystallization from a mixture of chloroform and ether gave white prisms melting at l7l-l74 dec. Ultraviolet maxima (2- propanol) at 227 mp. (e= 20.200). 277 mp. (e 8800), 282 mp (e 8750). inflexion at 292 mp. (e 7200); infrared absorption (KBr) at 1,660 cm.

Anal. Calcd. for C|7H;N- IO2: C. 72.84; H. 5.75; N. 9.99 Found: C. 73.07. H. 5.71; N. 9.83

The 2-[2'-(4-anisoyl)phenyll-2-imidazoline prepared in this manner can form the isomeric 2.3- dihydro--hydroxy-5-(4-methoxyphenyl)-5H- imidazo[2.l-a]isoindole.

EXAMPLE 17 Preparation of 2-[ 4'-chloro-2 '-benzoylphenyl ]-2-imidazoline To 2 ml. of ethylenediamine was added 0.9 g. of 2- benzoyl-4-chlorobenzaldehyde in small portions. The solution was stirred for 10 minutes. poured into ice water and the solid yellow precipitate was collected. This solid was dissolved in ether and shaken in air for minutes. A White precipitate was obtained which after recrystallization from a mixture of methylene chloride and methanol melted at 200202 dec. Ultraviolet maxima (2-propanol) at 242 mp. (e 17.500), 278 mp (e 3800). 286 mp (68 3300), inflexions at 270 mp. (e 3450), 295 mp. (e 2400); infrared absorption (KBr) at 1665 cm".

Anal. Calcd. for C,.;H,; ClN- -O: C. 67.49; H. 4.60

Found: C-. 67.42; H. 4.90

of toluene was refluxed for 18 hours. During this time 0.5 ml. of an aqueous phase had separated in a Dean Stark receiver. The mixture was concentrated in vacuo and the residual orange oil was dissolved in a mixture containing 15 ml. of ethanol. 15 ml. of methylene chloride and 1.5 ml. of a 30 per cent by weight aqueous solution of hydrogen peroxide. After stirring at 25 for 18 hours a white precipitate was collected which after recrystallization from methanol gave white needles melting at l87189 dec. Ultraviolet maxima (2-propanol) at 227 mp. (e 22.800), 259 mp. (e 4700). 275 mp (68 4800). inflexion at 292 mp. (e 2300); infrared absorption (KBr) at 1660 cm".

Anal. Calcd. for c H BrN- oz C. 58.37; H. 3.98 Found: C. 58.27; H. 3.75

The 2-[2-(4-bromobenzoyl)phenyl]-2-imidazoline prepared in this manner can form the isomeric 5-(4- bromophenyl)-2.3-dihydro-5-hydroxy-5H- imidazo[2,1-a]isoindole.

The hydrochloride was prepared by adding ethereal hydrogen chloride to a solution of 5-(4-bromophenyl)- 2,3-dihydro-5-hydroxy-5H-imidazo[2.l-a]isoindole in a mixture of methylene chloride and methanol. The precipitate was recrystallized from a mixture of ethanol and ether to give white prisms melting at ll58 dec. Ultraviolet inflexion (2-propanol) at 223 mp (e 20.000). maxima at 251 mp. (e 12.200) and 271 mp. (e 13.300); infrared absorption (KBr) at 1660 cm".

Anal. Calcd. for C H BrN QHCl: Cl. 9.70 Found: Cl. 9.82

EXAMPLE 19 Preparation of 2.3-dihydro-5-methoxy-5-phenyl-5H-imidazo[ 2, l a]isoindole hydrochloride A solution of 5 g. of 2-(2-benzoylphenyl)-2- imidazoline in 50 ml. of methanol was refluxed for 18 hours. The solution was concentrated in vacuo. dissolved in 20 ml. of methanol and ml. of ether was added. Crystals precipitated and were identified as starting material. The mother liquor was concentrated and the residue was recrystallized from a mixture of methanol. methylene chloride and ether to give the product as white prisms melting at l30-14l dec. Ultraviolet maxima (2-propanol) at 244 mp. (e 14,400) and 278 mu (6 5100); infrared absorption (KBr) at 1670 cm".

Anal. Calcd. for C H N- ,O.HCl: C. 67.83; H. 5.70;

OCH 10.32

Found: C. 67.84; H. 5.61;

OCH 10.44

The corresponding base was obtained as a colorless oil by liberating it from the hydrochloride obtained as above with alkali. Ultraviolet inflexions (0.1N KOH) at 230 mp. (6 14,600), 290 mp. (e 2700), maxima at 269 mu (6 4200) and 275 mp. (e 4600).

EXAMPLE 20 Preparation of 2.3,4.o-tetrahydro-o-phenylpyrimido[ 2. l-alisoindole sulfate A solution of 10.5 g. of 2-benzoylbenzaldehyde and 22 ml. of propylenediamine in 125 ml. of toluene was refluxed for 18 hours. During this time 4.5 ml. of an aqueous phase had separated in a Dean Stark receiver. The solution was concentrated in vacuo and the residue was recrystallized from a mixture of ethanol and petroleum ether to give white prisms melting at l70- 172 dec. Ultraviolet maximum (2-propanol) at 238 mp. (e 18,200). inflexions at'246 mp. (e= 16,000), 265 mp. (e ='5600). 276 my. (5 3400) and 285 mu (e 2100); infrared absorption (KBr) at 1675 cm".

Anal. Calcd. for CHH ..N .H SO.: C, 58

Found: C. 58. .4

EXAMPLE 21 Preparation of 2.3,4.S-tetrahydro-7-hydroxy-7-phenyl-7H-diazepino' [2. l--a]isoindole A solution of 10.5 gof 2-ben zoylbenzaldehyde and 28.5 ml. of 1,4-diaminobutane in 100 ml. of toluene The precipitate was collected and recrystallized from a I mixture of methanol and ether to give the oxalic acid salt as white prisms melting at ca. 200 dec. This salt was suspended in a mixture of aqueous sodium carbonate solution and methylene chloride. The methylene chloride solution was concentrated and the residue was recrystallized from a mixture of chloroform and ether to give .the product as white needles melting at 216-220 dec. Ultraviolet maxima (2-propanol) at 258 mp. 5000). 265 mu (.5: 5100), 273 mp. (a 4800). inflexions at 230 ma (6 15,000) 290 mp. (e 2400); infrared absorption (KBr) at 1.650 cm;

Anal. Calcd. for C H MO: (5.77.67; Foundz c. 77.64;

EXAMPLE 22 Preparation of 2-(2-aminoethyl)-3-phenylphthalimidine A solution of25 g. (0.1 mole) of l,2,3,9b-tetrahydro- 9b-phenyl-5H-imidazo[2,1-a]isoindol-5 one in 150 ml.

of acetic acid containing 2.5 g. of hydrogen chloride was shaken under one atmosphere of hydrogen at 25 using 0.5 g. of platinum oxide as catalyst. in the course of 7 hours. 3,000 ml. of hydrogen (theory ca. 2,500 ml.) was absorbed and the rate of uptake had slowed down considerably. The solution was poured into ice waten'basified with ammonia and extracted with methylene chloride. The organic phase was dried and concentrated. The residue crystallized with ether and after recrystallization from a mixture of methylene chloride and petroleum ether gave white prisms of 2-(2- aminoethyl )-3-phenylphthalimidine melting at 9093. y 1685 cm, )t,,,.,,""" 247 mu, 6 6000, 279 mu. e 1900.

EXAMPLE 23 Preparation of 2-[ 2 2-chlorobenzoyl )phenyl l-2-imidazoline To 250 ml. of concentrated sulfuric acid was added. with stirring and slight cooling. 375g. (0.545 mole) of sodium nitrite. To this was added 120.5 g. (0.50 mole) of 2-(2-arninobenzoyl)benzoic acid at such a rate that the temperature of the reaction mixture remained between 30*40. After the addition was complete the reaction mixture was stirred for lhour and then poured into one liter of ice and water and filtered. The filtrate was added rapidly to a stirred solution of g. (0.555 mole) of cuprous chloride. 150 g. of sodium chloride. 250 ml. ofconcentrated hydrochloric acid and 300 ml. of water. Thev precipitated gum was extracted with chloroform and the extracts were washed twice with water. dried over anhydrous sodium sulfate and evaporated under vacuo to leave a red oil which crystallized .upon stratching. Recrystallization from 200 ml. of ethyl acetate gave 2-(2-chlorobenzoyl)benzoic acid as a pink solid. A sample recrystallized three times from ethyl acetate gave colorless prisms. double m.p. 1 l2-l 16 and Ether (400 ml.) was added followed by the slow addition of ml. of water. with ice cooling. The mixture bined filtrates were evaporated under vacuo to a yellow oil which crystallized upon scratching. The material was recrystallized from 150 ml. of isopropyl ether to give 2-cliloro2'-hydroxymethylbenzhydrol as a slightly pink solid, mp. 87. A sample was recrystallized three times from isopropyl ether to give colorless prisms, m.p. 8687.

A 2-liter. 3-necked, round bottom flask was fitted with a mechanical-stirrer, dropping funnel and a Dean- Stark trap fitted with a condenser. A mixture of 4 l .7 g. (0.376 mole) of selenium dioxide in ml. of acetic hour. a solution of 74.4 g. (0.3 mole) of 2-chloro-2- hydroxymethylbenzhydrol prepared as above in 85 ml. of acetic acid and 250 ml. of xylene. The Dean-Stark trap was cooled during this time to promote separation of an aqueous phase. About 60 ml. of the aqueous phase was separated during 5 hours. The reaction mixture was refluxed for a total of 22 hours. cooled and flltered. The filtrate was added to 800 ml. of ice and water', made alkaline with 50 per cent sodium hydroxide and the mixture extracted with 600 ml. of ether. The extracts were washed with water. dried over anhydrous sodium sulfate and evaporated to yield an orange oil which could not be crystallized. Vapor phase chromatographic analysis showed the presence of two compounds.

45.4 Grams of the oil. 52.5 g. (0.875 mole) of ethylenediamine and 400 ml. of benzene were refluxed for 5 hours in a round bottomed flask equipped with a Dean-Stark trap and a condenser. About 6 ml. of aqueous phase separated in the trap. The reaction mixture was cooled. washed three times with saturated aqueous salt solution and dried over anhydrous sodium sulfate. Air was then bubbled through the benzene solution for hours but only a small amount of solid separated.

The benzene was removed under vacuo and the residue was dissolved in 150 ml. of ethanol and 40 ml. (0.350 mole) of 30 per cent hydrogen peroxide. After stirring for 3 hours the ethanol was removed under vacuo and 300 ml. of benzene was added to the residue. The aqueous phase was separated and the benzene so lution was dried over anhydrous sodium sulfate and evaporated under vacuo to leave a pale yellow oil.

Ether (150 ml.) was added and a crystalline solid separated. The mixture was filtered to give a pale yellow solid. m.p. l64-l67 dec. The ether filtrate was stirred at room temperature. exposed to air, for two days. The precipitated solid was filtered to give an additional pale yellow solid. Thin layer chromatography of the combined solids showed the presence of one major component. Rf 0.41, and a minor component. Rf 0.67. The latter component was 2,3-dihydro-5-hydroperoxy-5-(oc'hlorophenyl)-5H-imidazo[2,l-a]-isoindole since the yellow solid precipitated iodine from a saturated methanolic potassium iodide solution.

To a suspension of the yellow solid in 60 ml. of refluxing methanol was added a solution of 4.28 g. (0.017 mole) of Na SO 7H. ,O in 30 ml. of water over a period of 5 minutes. After refluxing for 15 minutes longer the reaction mixture was cooled and filtered. The filtered solid was washed 3 times with ml. of water and dried. Recrystallization from methanol-chloroform gave 2-[2-(2-chlorobenzoyl)phenyl]-2-imidazoline as colorless prisms. m.p. l80-l8l dec.

Anal. CtllCd. for c m cm o: c. 67.49; H. 4.60; N. 9.244 Found: c. 67.l5; H. 4.56; N. 9.66

28 methanolic hydrogen chloride and 35 ml. of methanol was added 200 ml. of ether and the solution cooled. Fil tration gave 2-[2-(2-chlorobenzoyl)-phenyl]-2- imidazoline hydrochloride. m.p. l78l80 dec. Dilution of the mother liquors with 200 ml. of ether followed by cooling and filtering afforded an additional quantity of hydrochloride. Recrystallization from methanoI-ether gave colorless prisms. m.p. 178l80 dec.

Anal. Calcd. for C .;H Cl:N O: Cl.

Found: Cl.

EXAMPLE 24 A solution of 7.5 g. of phthalaldehydic acid in 30 ml. of ethanol and 34 ml. of ethylenediamine was refluxed for 16 hours. The solution was concentrated in vacuo and the residue was dissolved in methylene chloride. The solution was washed with water. dried and concentrated. The residue was distilled in a bulb tube at 0.3 mm at a bath temperature of l50l 80. A colorless oil was obtained which was dissolved in methanol and on addition of ethereal hydrogen chloride gave white prisms of l.2.3.9b-tetrahydro-5H-imidazo[2,1- a]isoindol-S-one hydrochloride, m.p. 222224 dec.

The salt obtained in the preceding experiment was treated with aqueous potassium carbonate solution. Extraction with methylene chloride gave an oil of which 0.9 g. was dissolved in a mixture of 25 ml. of benzene and 10 ml. of ether. To this solution was added 5.5 ml. of a 2 N solution of phenyl lithium in a mixture of benzene and ether (7:3 After stirring at 25 for 1 hour the solution was poured into ice water and extracted with ethyl acetate. This solution was concentrated and the residue was exposed to air for 48 hours. On addition of methylene chloride crystals were obtained which were dissolved in methanol. Addition of ethereal hydrochloric acid gave white prisms which after recrystallization from a mixture of methanol and ether gave crystals melting at 173l75 dec. This material was identical with authentic 2-(Z-benzoylphenyl)-2-imidazoline hydrochloride.

We claim:

1. A compound of the formula:

wherein B represents an alkylene chain of 2 carbon atoms in which one or more of the hydrogens can be replaced by lower alkyl; and R R R and R are each 29 30 independently selected from the group consisting of hy- 3. The compound according to claim 1 wherein R,, g f halogem lower y alkoxk y y- R and R are each hydrogen and R is chloro and is and tnfluommethyl' in 4-position and B is ethylene. i.e., the compound 2. The compound according to claim 1 wherein R R R and R are each hydrogen and B is ethylene. i.e., 5 the compound 2,3-dihydr0-5-hydroperoxy-5-phenyl- 5H-imidazo[2.l-a]-isoindole.

(p-chlorophenyl )-2,3-dihydro-S-hydroperoxy-S H- imidazo[2il-a]isoindole. 

1. A COMPOUND OF THE FORMULA:
 1. A compound of the formula:
 2. The compound according to claim 1 wherein R1, R2, R3, and R4 are each hydrogen and B is ethylene, i.e., the compound 2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo(2,1-a)-isoindole. 